“
“The global incidence of fatty liver disease (FLD) has eclipsed

nearly every other hepatic pathology, largely due to the obesity epidemic. Steatosis is the first requisite step in progression to steatohepatitis and cirrhosis, the more severe forms of FLD. Lifestyle changes remain the most effective treatment for FLD; however, waistlines continue to expand in parallel with a booming weight-loss industry, indicating that lifestyle changes are both difficult to achieve and ineffective for many patients. Thus, targets for therapeutic intervention are sought. A study in this issue of Hepatology[1] suggests a novel pathway that contributes to steatosis, opening new avenues for designing drugs to alleviate FLD. Many investigators studying hepatic injury have A769662 focused on the role of reactive oxygen species (ROS), such as hydrogen

peroxide (H2O2). High levels of ROS can result in severe cell dysfunction or death. Some studies suggest that ROS can cause FLD, while many others focus on the consequence of ROS once FLD has formed. Promising results from clinical trials using antioxidants in patients with nonalcoholic[2] and alcoholic[3] FLD (i.e., nonalcoholic fatty liver disease [NAFLD] and alcoholic liver disease [ALD], respectively) Mitomycin C support the theory that ROS can cause steatosis as well as the hepatic injury associated with FLD. The work by Nussbaum et al.[1] in this issue of Hepatology challenges this theory by demonstrating a paradoxic role for ROS in FLD: instead of contributing

to the pathogenesis of FLD, low (i.e., homeostatic) levels of ROS appear to prevent steatosis and addition of antioxidants promotes steatosis. Moreover, they uncover a previously unrecognized link between purine metabolism, ROS, and regulation of lipid droplet formation and utilization in hepatocytes. This study benefited from the use of zebrafish, a small vertebrate with high reproductive capacity and a fully sequenced genome that shows high conservation with humans.[4] The larval liver has a cellular composition comparable to mammals, and their hepatocytes all can synthesize, store, and metabolize lipids. Thus, zebrafish, like mammals, get FLD.[5] These attributes make zebrafish the only vertebrate amenable to forward genetic screening, which provides an unbiased approach to identify novel genes involved in FLD. Additionally, zebrafish larvae are transparent, providing an unparalleled view inside of the growing organism. The authors capitalize on this feature to develop a novel means to measure steatosis. Confocal imaging of the liver sections of larvae, where the contours of the hepatocytes are outlined with green fluorescent protein (GFP) and a fluorescent dye that labels the lipid droplets, allows quantification of cells containing lipid droplets as well as the number of droplets per cell, and also generates exquisite 3D images, rendering this pathology at subcellular resolution.